[Research progress on pathogenesis of malignant mesothelioma].

The occurrence of malignant mesothelioma is related to exposure of asbestos. And many researchers have conducted in-depth analysis of the molecular changes of mesothelioma, showed that its molecular characteristics were chromosome changes, including chromosome rearrangement, gene mutation and gene deletion. Recent studies have strengthened our understanding of molecular characterization of mesothelioma, such as targeted mutations of tumor suppressor genes, differential gene expression, changes of miRNA and signal pathways. It is of great significance for the early diagnosis, clinical treatment and prognosis of malignant mesothelioma to explore the pathogenesis and development of malignant mesothelioma. This article reviews the research progress on the pathogenesis and carcinogenesis-related molecules of malignant mesothelioma.

[Development and validation of prognostic nomogram for malignant pleural mesothelioma].

Objective: To development the prognostic nomogram for malignant pleural mesothelioma (MPM). Methods: Two hundred and ten patients pathologically confirmed as MPM were enrolled in this retrospective study from 2007 to 2020 in the People's Hospital of Chuxiong Yi Autonomous Prefecture, the First and Third Affiliated Hospital of Kunming Medical University, and divided into training (n=112) and test (n=98) sets according to the admission time. The observation factors included demography, symptoms, history, clinical score and stage, blood cell and biochemistry, tumor markers, pathology and treatment. The Cox proportional risk model was used to analyze the prognostic factors of 112 patients in the training set. According to the results of multivariate Cox regression analysis, the prognostic prediction nomogram was established. C-Index and calibration curve were used to evaluate the model's discrimination and consistency in raining and test sets, respectively. Patients were stratified according to the median risk score of nomogram in the training set. Log rank test was performed to compare the survival differences between the high and low risk groups in the two sets. Results: The median overall survival (OS) of 210 MPM patients was 384 days (IQR=472 days), and the 6-month, 1-year, 2-year, and 3-year survival rates were 75.7%, 52.6%, 19.7%, and 13.0%, respectively. Cox multivariate regression analysis showed that residence (HR=2.127, 95% CI: 1.154-3.920), serum albumin (HR=1.583, 95% CI: 1.017-2.464), clinical stage (stage Ⅳ: HR=3.073, 95% CI: 1.366-6.910) and the chemotherapy (HR=0.476, 95% CI: 0.292-0.777) were independent prognostic factors for MPM patients. The C-index of the nomogram established based on the results of Cox multivariate regression analysis in the training and test sets were 0.662 and 0.613, respectively. Calibration curves for both the training and test sets showed moderate consistency between the predicted and actual survival probabilities of MPM patients at 6 months, 1 year, and 2 years. The low-risk group had better outcomes than the high-risk group in both training (P=0.001) and test (P=0.003) sets. Conclusion: The survival prediction nomogram established based on routine clinical indicators of MPM patients provides a reliable tool for prognostic prediction and risk stratification.

[Efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitors treatment failure].

Objective: To investigate the efficacy and influencing factors of immunotherapy combined with chemotherapy and bevacizumab in patients with non-small cell lung cancer (NSCLC) who failed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. Methods: A retrospective analysis was made on the clinical data of 60 NSCLC patients who were treated with immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure in the Affiliated Cancer Hospital of Shandong First Medical University from January 2019 to March 2022. Patients were followed up by telephone or outpatient review up to October 1, 2022, with a median follow-up of 8.2 months (95%CI: 7.1-9.3). All 60 patients were followed up. The response evaluation criteria in solid tumors were used to evaluate the short-term efficacy. The adverse reactions of patients were evaluated according to the common terminology criteria for adverse events. The survival curve was drawn by Kaplan-Meier method. Cox proportional hazard regression models were utilized to analyze the influencing factors of progression-free survival (PFS). Results: Among the 60 NSCLC patients, 22 were males. The age ranged from 41 to 75 years, with a median age of 61 years. Eleven patients had partial response, 19 patients had stable disease and 30 patients had progressive disease. The median PFS was 8.2 months (95%CI: 7.2-9.2). The median PFS of patients with low expression of programmed death receptor-ligand 1 (PD-L1) [Tumor cell Proportion Score (TPS)<1%], moderate expression of PD-L1 (1%≤TPS≤49%), and high expression of PD-L1 (TPS≥50%) were 6.4 (95%CI: 4.8-8.0), 8.3 (95%CI: 7.3-9.3) and 10.6 months (95%CI: 7.2-14.1), respectively, and there were statistically significant differences (χ2=13.58, P<0.001). Multivariate Cox proportional risk regression model analysis showed that age>65 years old (HR=4.017, 95%CI: 1.468-10.992, P=0.007) was a risk factor for PFS in NSCLC patients who received immunotherapy combined with chemotherapy and bevacizumab after EGFR-TKIs treatment failure. Moderate expression of PD-L1 (HR=0.360, 95%CI: 0.139-0.930, P=0.035) and high expression of PD-L1 (HR=0.155, 95%CI: 0.039-0.625, P=0.009) were protective factors for PFS. Most of the treatment-related adverse reactions in the whole group were grade 1-2, including bone marrow suppression (n=24), nausea (n=25), decreased appetite (n=24), fatigue (n=22), vomiting (n=18), abnormal liver function (n=17), blood creatinine increased (n=10), and so on. These were tolerated by the patients. Conclusions: NSCLC patients who failed EGFR-TKIs treatment can tolerate adverse reactions related to immunotherapy combined with chemotherapy and bevacizumab treatment. PFS is significantly prolonged in those aged≤65 years and those with moderate and high expression of PD-L1.

[Gastrointestinal ALK-positive anaplastic large cell lymphoma: a clinicopathological analysis of five cases].

Objective: To investigate the clinicpathological characteristics of ALK-positive anaplastic large cell lymphoma (ALCL) of the gastrointestinal tract, and to discuss its diagnosis and differential diagnosis. Methods: Five cases of gastrointestinal ALK-positive ALCL diagnosed and treated in Xijing Hospital of the Fourth Military Medical University, between 2011 and 2019 were collected. There were three male and two female patients, aged 5-42 years (mean 25 years). These patients clinically presented with fever and night sweats, weight loss, abdominal pain, abdominal mass, ulcers, bleeding, or intestinal obstruction, and underwent surgical resection of the tumors or endoscopic biopsy. The clinical manifestations, auxiliary examinations, histopathological characteristics, immunophenotypes and genetic alterations were analyzed. Results: In this cohort, one case was common type, two cases were monomorphic variant of common type, and two cases were small cell variant. The tumor cells in all cases expressed ALK, CD30, and one or more T lymphocyte markers, while all the markers of B lymphocyte and plasmacyte were negative. Clonality analysis showed that two cases had clonal T cell receptor (TCR) and immunoglobulin (Ig) gene rearrangement, one case had no clonal TCR but Ig gene rearrangement, and one case had no clonal TCR and Ig gene rearrangements. During the 4 to 67 months' follow-up, two patients died of the disease, two were alive with free of disease and one had a relapse. Conclusions: ALK-positive ALCL of the gastrointestinal tract is extremely rare, and has poor prognosis. Lymphoma originating from this site with CD30 and ALK-positive phenotypes may be considered to be ALCL; however differentiation from other tumors that had anaplastic features, expressed CD30 and or ALK, in particular, ALK positive large B-cell lymphoma is necessary.

[Malignant gastrointestinal neuroectodermal tumor: a clinicopathological analysis of three cases].

Objective: To investigate the clinicopathological characteristics of malignant gastrointestinal neuroectodermal tumors (GNET), and to describe their clinical, histological, immunophenotypic, ultrastructural, and molecular features, diagnosis and differential diagnosis. Methods: Three cases of malignant GNET were collected at Xijing Hospital of the Fourth Military Medical University, from 2013 to 2022. All patients underwent surgical resection of the tumor. Histological, immunohistochemical (IHC), ultrastructural and molecular genetic analyses were performed, and the patients were followed up for six months, three years and five years. Results: There were two males and one female patients. The tumors were located in the ileum, descending colon, and rectum, respectively. Grossly, the tumors were solid, firm, and poorly circumscribed, measured in size from 2 to 4 cm in greatest dimension, and had a greyish-white cut surface. These tumors were histologically characterized by a sheet-like or nested population of oval to spindled cells or epithelioid cells with weakly eosinophilic or clear cytoplasm, small nucleoli and scattered mitoses. Electron microscopy showed neuroendocrine differentiation, and no evidence of melanogenesis. IHC staining showed that the tumor cells were diffusely positive for S-100 protein, SOX10, CD56, synaptophysin and vimentin. They were negative for melanocytic markers, HMB45 and Melan A. All three cases showed split EWSR1 signals consistent with a chromosomal translocation involving EWSR1. Next-generation sequencing in one case confirmed the presence of EWSR1-ATF1 fusion. These patients were followed up for 6 months, 3 years and 5 years, respectively, and all of them developed possible lung or liver metastases, and one of them died of multiple pulmonary metastases. Conclusion: Malignant GNET has distinctive morphological, IHC, and molecular genetic features and it should be differentiated from other malignancies of the gastrointestinal tract, especially clear cell sarcoma and melanoma.

[The value of cardiac MRI in the risk stratification in patients with hypertrophic cardiomyopathy].

Objective: To explore the value of cardiac magnetic resonance imaging (CMR) in the risk stratification of hypertrophic cardiomyopathy (HCM). Methods: HCM patients who underwent CMR examination in Fuwai Hospital between March 2012 and May 2013 were retrospectively enrolled. Baseline clinical and CMR data were collected and patient follow-up was performed using telephone contact and medical record. The primary composite endpoint was sudden cardiac death (SCD) or and equivalent event. The secondary composite endpoint was all-cause death and heart transplant. Patients were divided into SCD and non-SCD groups. Cox regression was used to explore risk factors of adverse events. Receiver operating characteristic (ROC) curve analysis was used to assess the performance and the optimal cut-off of late gadolinium enhancement percentage (LGE%) for the prediction of endpoints. Kaplan-Meier and log-rank tests were used to compare survival differences between groups. Results: A total of 442 patients were enrolled. Mean age was (48.5±12.4) years and 143(32.4%) were female. At (7.6±2.5) years of follow-up, 30 (6.8%) patients met the primary endpoint including 23 SCD and 7 SCD equivalent events, and 36 (8.1%) patients met the secondary endpoint including 33 all-cause death and 3 heart transplant. In multivariate Cox regression, syncope(HR=4.531, 95%CI 2.033-10.099, P<0.001), LGE% (HR=1.075, 95%CI 1.032-1.120, P=0.001) and left ventricular ejection fraction (LVEF) (HR=0.956, 95%CI 0.923-0.991, P=0.013) were independent risk factors for primary endpoint; Age (HR=1.032, 95%CI 1.001-1.064, P=0.046), atrial fibrillation (HR=2.977, 95%CI 1.446-6.131, P=0.003),LGE% (HR=1.075, 95%CI 1.035-1.116, P<0.001) and LVEF (HR=0.968, 95%CI 0.937-1.000, P=0.047) were independent risk factors for secondary endpoint. ROC curve showed the optimal LGE% cut-offs were 5.1% and 5.8% for the prediction of primary and secondary endpoint, respectively. Patients were further divided into LGE%=0, 0

[Analysis of clinicopathological features of 68 cases of malignant pleural mesothelioma].

Objective: To analyze the clinicopathological characteristics of diffuse malignant pleural mesothelioma (MPM), and explore the diagnostic methods in order to improve the early diagnosis rate. Methods: In January 2019 to January 2022, the clinical features, auxiliary examination and immunohistochemical results of 68 cases of MPM were analyzed retrospectively. The pathogenic features, histopathological morphology and the expression of related antibodies including Calretinin (CR), D2-40 and WT-1 were summarized. Results: Among the 68 patients, 40 male (58.82%), 28 female (41.18%), male to female ratio was 1.43%, median age was 58 years old; 50% of patients in Dayao County, epithelial mesothelioma 59 cases (86.76%), occurred in right chest in 39 cases (57.35%), left chest in 25 cases (36.76%), and 4 cases in both sides (5.89%). The most common initial clinical manifestations were pleural effusion (95.59%), chest pain (36.75%), chest tightness and shortness of breath (30.88%). The main imaging findings were pleural effusion in 49 cases (98.00%) and pleural thickening in 46 cases (92.00%). MPM tumor cells often expressed Calretinin, CK5/6, WT1 and D2-40, while TTF-1, NapsinA and CEA, the main markers differentiated from lung adenocarcinoma were negative. Serum CYFRA21-1 and CEA have high value in differential diagnosis of benign and malignant pleural effusions. Conclusion: Diffuse MPM has diverse histological and cytological morphology, which needs to be differentiated from a variety of diseases. Correct diagnosis of diffuse MPM through immunohistochemistry requires the combined application of a group of Mesothelium related antibodies.

[Causal inference methods and its application in the study of health effects of air pollution].

The adverse health effects of air pollution remains a daunting public health problem globally. The research of the health effects of air pollution provides important evidence for ambient air quality standard establishments and air pollution interventions. In recent years, causal inference has been gradually introduced into the observational study of environmental epidemiology, which provides more statistical method options for the study of causal relationships between air pollution and population health effects. Controlling confounders in observational studies is a major challenge for causal inference. This study introduces the causal inference methods for the identification and control of confounding factors currently used in the study of air pollution and population health effects, in order to provide methodological reference and basis for the causal inference study of air pollution and population health effects in China.

[HBx promotes ubiquitination and degradation of ZO1 and increases the migration and invasion of liver cancer cells].

Objective: To study the effect of hepatitis B virus X protein (HBx) expression level on migration and invasion of zonula occludens protein-1 (ZO-1) in HepG2 liver cancer cells. Methods: Liver cancer cells were transfected with HBV full gene plasmid (pcDNA3.1-HBV1. 1 or pcDNA3.1-HBV1.3), empty plasmid (pcDNA3.1) and HBV-encoded protein plasmids (pHBc, pHBs, pHBp and pHBx), respectively. Western blot and RT-PCR were used to detect ZO1 protein and mRNA levels. Immunoprecipitation was used to detect transfected pHBx. Western blot was used to detect ZO1 ubiquitination levels. Transwell chambers were used to assess cell migration and invasion. Cell proliferation and lactate dehydrogenase assay was used to detect siRNA transfecting targeting ZO1. Flow cytometry was used to detect cell apoptosis and cycle. The data was compared between two and multiple groups by using an independent sample t-test and one-way analysis of variance. Results: Compared with the empty plasmid, ZO1 protein level in HepG2 cells after transiently transfected with pHBV1.1 and pHBV1.3 was decreased by 42.99% ± 6.8% and 55.0% 5 ± 4.56%, respectively, and their mRNA levels did not change significantly. ZO1 protein level in Huh7 cells was decreased by 17.46% ± 4.94% and 47.53% ± 3.38%, respectively. ZO1 protein level after transfection with pHBx was decreased by 47.02% ± 3.4%, while the ZO1 protein level after transfection with pHBc, pHBs and pHBp did not change significantly. ZO1 mRNA level was unaffected with pHBx transfection. ZO1 ubiquitin level and cell migration and invasion ability in HepG2 cells was significantly increased with transfected pHBx. HepG2 cells proliferation, apoptosis and cycle after transfection with ZO1-targeted siRNA did not change significantly, but the migration and invasion ability were significantly increased. Conclusion: HBx can increase the migration and invasion of liver cancer cells by promoting the ubiquitination and degradation of ZO1 protein level.

[Role of cardiac magnetic resonance imaging in myocarditis patients with biopsy negative: a retrospective case series study].

Objective: To analyze the cardiac magnetic resonance (CMR) imaging feature of clinically diagnosed myocarditis patients with negative endocardial biopsy (EMB) results, and to further demonstrate the diagnostic value of CMR in these patients. Methods: This was a retrospective case series study. Fourteen patients, who were clinically diagnosed as myocarditis according to 2013 European Society of Cardiology (ESC) clinical diagnostic criteria for myocarditis, but with negative EMB results, were enrolled. All patients underwent CMR examinations. The morphological, functional and histological changes of the heart were assessed based on black blood sequence, cine sequence, T2W-STIR sequence and contrast agent late gadolinium enhancement,(LGE). Results: There were 10 males and 4 females in this cohort, the age was (25.6±13.2) years. The interval between symptom onset and CMR was 21 (13, 60) days, and the interval between symptom onset and EMB was 19 (9, 40) days. There were 13 patients with abnormal CMR results including myocardial oedema, fibrosis, decreased ejection fraction, pericardial effusion or increased cardiac chamber dimension. Nine out of 14 patients had CMR morphological and/or functional abnormalities, including 1 case of left atrium enlargement, 1 case of left ventricle enlargement, 3 cases of right ventricle enlargement, 4 cases of increased left ventricular end diastolic volume index. Left ventricular ejection fraction was<50% in three cases, right ventricular ejection fraction was<40% in 5 cases, and pericardial effusion depth>3 mm was detected in 3 cases. Of the 14 patients, 11 had histological changes, of which 6 had T2 ratio≥2. Among the 10 patients (10/14) with positive LGE, the most common patterns were subepicardial LGE of the lateral wall and/or midwall LGE of the septum (n=9); 2 cases showed extensively subendocardial LGE of the left ventricular wall. No LGE involved in the right ventricular wall in the whole cohort. Conclusion: CMR plays a complementary role in the diagnosis of myocarditis in clinically diagnosed myocarditis patients with negative EMB findings.

[Radiation dose and image quality of noncontrast chest CT in domestic and imported main stream manufacturers].

Objective: To compare the radiation dose and image quality of noncontrast chest CT and detection of ground-glass opacity pulmonary nodules (GGN) in domestic 128-slice spiral CT with the other CT scanners from three main stream manufacturers. Methods: From May 8, 2018 to October 31, 2018, noncontrast chest CT images from Neusoft 128-slice CT (75 males, 25 females, (42±16) years), dual-source 64-slice CT (53 males, 47 females, (50±16) years) and dual-source 128-slice CT scanners(69 males, 31 females, (62±17) years), Toshiba 128-slice CT (51 males, 49 females, (58±13) years) and GE 128-slice CT scanner (55 males, 45 females, (60±10) years) were collected in Eastern Theater Command and Tianjin People's Hospital. Radiation dose and image quality were evaluated.GGN detected both in Neusoft CT and dual-source CT scanners were used to analyze the displaying ability of lesions. Results: The noise in lung window of Neusoft CT ((37.8±4.9) HU) was higher than that of other mainstream CT scanners, and the noise in mediastinal window ((8.4±1.9) HU) was lower than that of GE 128-slice CT ((9.8±3.2) HU), but higher than that of dual-source CT and Toshiba 128-slice CT ((6.9±3.5)HU) (P<0.05). The absolute value of lung SNR in Neusoft CT was lower than that of other mainstream CT scanners, and the SNR in aorta (4.6±1.3) was lower than those of dual-source CT and Toshiba 128-slice CT(6.8±2.2) (P<0.05), but was not statistically significant compared with GE 128-slice CT (5.0±1.7). The mean CT value of upper lung ((-863±31) HU) at Neusoft CT was higher than 128-row dual-source CT ((-869±35) HU), and the mean CT value of aorta ((37±7) HU) was lower than that of Toshiba 128-slice CT((42±7) HU) and GE 128-slice CT ((45±9) HU) (P<0.05), while the mean CT values of the remaining lung and aorta were not statistically significant (P>0.05). The two readers had good to excellent consistency for image quality in five scanners (the highest kappa value=0.984). The delineation ability of Neusoft CT for GGN boundary was lower than that of dual-source CT (P<0.05), but had similar abilities to display the solid components, lobulation, burring, vacuoles, vascular bundle sign and pleural depression sign of GGN (all P>0.05). Radiation dose of Neusoft CT was lower than Toshiba 128-slice CT, but higher than dual-source 64-sliceCT and GE 128-slice CT scanners (P<0.05). Conclusions: With lower radiation dose than Toshiba 128-slice CT, Neusoft CT chest examination can meet the requirements of clinical diagnosis, but higher radiation dose and the lower image quality than dual-source CT and GE 128-slice CT shown in this study indicate further improvement is needed in terms of software and hardware.

[Spindle cell/sclerosing rhabdomyosarcoma: a clinicopathological study of 20 cases].

Objective: To study the clinicopathological features and immunophenotype of spindle cell/sclerosing rhabdomyosarcoma (SRMS) in adults and children, as well as its correlation with the expression and gene-mutations of MYOD1. Methods: Twenty cases of SRMS were collected at Xijing Hospital, Fourth Military Medical University from 2009 to 2019. These cases were evaluated for clinical, pathological, and immunohistochemical features. MYOD1 gene sequencing was performed on 12 cases with available tissue and sufficient DNA quantity using Sanger sequencing. Results: The 20 patients included 12 children and 8 adults, 11 males and 9 females, with an age range of 8 months to 85 years (mean 22 years). Most of them presented with a painless, progressively enlarged solid mass. The tumors occurred in head and neck (7 cases), abdominal and pelvic cavity (7 cases, including 4 in abdominal cavity, 2 in pelvic cavity, 1 in abdominal and left thoracic cavity), upper limb (5 cases, including 2 in left shoulder, 1 in right armpit, 1 in right humerus, and 1 in left forearm), and the back (1 case). The diameter of these tumors ranged from 2.5 to 20 cm, with a mean of 6.2 cm. Histologically, all of the tumors were mainly composed of spindle cells arranged in fascicles, and in 7 cases, at least in part, arranged in herringbone pattern, resembling adult fibrosarcoma. Foci reminiscent of interstitial sclerosing were presented in 4 cases, pseudovascular structures in 2 cases, loosely myxoid stroma in 4 cases, and varying degree of necrosis in 9 cases. A various number of spindled or polygonal rhabdomyoblasts were observed between spindle cells in 3 cases.Among them,16 cases showed spindle cell morphology, 2 cases showed scleroisng morphology, and 2 cases showed a hybrid phenotype of spindle, sclerosing and primitive undifferentiated areas. Immunohistochemically, the tumor cells were positive for desmin, Myogenin and/or MyoD1, but negative for CKpan, ALK1, CD34, EMA, HMB45, SMA, H-cald and S-100. Four cases (4/12) harbored a homozygous or heterozygous MYOD1 (p.L122R) mutation. MYOD1-mutant SRMS usually had diffuse and strong nuclear MyoD1 positivity. Follow-up was available in 12 cases, ranged from 1 to 51 months. At the end of follow-up period, 3 patients died of the disease, 3 patients developed local recurrences, 2 patients survived with disease. Conclusions: SRMS is a rare type of rhabdomyosarcoma, and more commonly occurs in the head and neck of children than adults. MYOD1-mutant SRMS usually had diffuse and strong nuclear MyoD1 positivity, frequently associated with a more aggressive behavior.

[Establishment and clinical testing of pancreatic cancer Faster R-CNN AI system based on fast regional convolutional neural network].

Objective: To investigate the effectiveness of an enhanced CT automatic recognition system based on Faster R-CNN for pancreatic cancer and its clinical value. Methods: In this study, 4 024 enhanced CT imaging sequences of 315 patients with pancreatic cancer from January 2013 to May 2016 at the Affiliated Hospital of Qingdao University were collected retrospectively, and 2 614 imaging sequences were input into the faster R-CNN system as training dataset to create an automatic image recognition model, which was then validated by reading 1 410 enhanced CT images of 135 cases of pancreatic cancer.In order to identify its effectiveness, 3 750 CT images of 150 patients with pancreatic lesions were read and a followed-up was carried out.The accuracy and recall rate in detecting nodules were recorded and regression curves were generated.In addition, the accuracy, sensitivity and specificity of Faster R-CNN diagnosis were analyzed, the ROC curves were generated and the area under the curves were calculated. Results: Based on the enhanced CT images of 135 cases, the area under the ROC curve was 0.927 calculated by Faster R-CNN. The accuracy, specificity and sensitivity were 0.902, 0.913 and 0.801 respectively.After the data of 150 patients with pancreatic cancer were verified, 893 CT images showed positive and 2 857 negative.Ninety-eight patients with pancreatic cancer were diagnosed by Faster R-CNN.After the follow-up, it was found that 53 cases were post-operatively proved to be pancreatic ductal carcinoma, 21 cases of pancreatic cystadenocarcinoma, 12 cases of pancreatic cystadenoma, 5 cases of pancreatic cyst, and 7 cases were untreated.During 5 to 17 months after operation, 6 patients died of abdominal tumor infiltration, liver and lung metastasis.Of the 52 patients who were diagnosed negative by Faster R-CNN, 9 were post-operatively proved to be pancreatic ductal carcinoma. Conclusion: Faster R-CNN system has clinical value in helping imaging physicians to diagnose pancreatic cancer.

Safety, efficacy and tumor mutational burden as a biomarker of overall survival benefit in chemo-refractory gastric cancer treated with toripalimab, a PD-1 antibody in phase Ib/II clinical trial NCT02915432.

BACKGROUND: High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1. PATIENTS AND METHODS: We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1-d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy. RESULTS: In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group [14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24-0.96), P = 0.038], while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs. CONCLUSIONS: Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent. TRIAL REGISTRATION: ClinicalTrials.gov NCT02915432.

[Research on the effect of biological glue on augmenting the viscosity of tissue engineering retinal nerve scaffolds].

Objective: To evaluate the adhesion effect of tissue engineering retinal nerve scaffolds modified with biological glue. Methods: Experimental study. To fabricate a biological glue by blending laminin, collagen Ⅳ, entactin and HSPG(2) with phosphate-buffered saline (PBS) buffer solution, scaffolds were then modified with the biological glue of various concentration levels (10 µl/cm(2), 20 µl/cm(2), 30 µl/cm(2) and 40 µl/cm(2)). The effects of various concentration levels glue on inducing scaffold adhesion were analyzed after 24 h. Cell count method and CCK-8 kit were used to assess the effects of biological glue on cell growth and toxicity. Then the scaffolds modified with or without glue were transplanted into rabbit's retina by 23 G pars plana vitrectomy. Intraocular pressure(IOP) and retina examination were assessed by ICare, fundus photograph and OCT. The adhesion effects of various concentration levels glue were analyzed by chi-square test. The cell adhesion rate of different scaffolds was analyzed by Mann-Whitney U test. One-Way ANOVA was used to compare the cell survival rate of different scaffolds. After transplantation, the IOP variance of rabbits was analyzed by repetitive measurement deviation analysis. Results: Compared with the control groups, the maximum adhesion rate of the biological glue was 91.7% (χ(2)=8.79, P<0.05) at 30µl/cm(2) concentration level. After 24h of cultivation, cell adhesion rate of glue-scaffold group (86.85%) was significantly higher than that of pure scaffold group (13.78%, U=0.01, P<0.05), while there was no significant difference between the cell survival rates of the two groups (F=7.235, P=0.11). There was no significant difference (F=79.16, P=0.07) between the IOP of viscosity modified group [(18.4+0.93) mmHg (1 mmHg=0.133 kPa)] and non- modified group [(17.1±0.04)mmHg]. The retina adhesion rate of viscosity modified scaffold was 80% at 7 days postoperatively, and the fundus examination showed no inflammatory response in retina and vitreous cavity. Conclusion: This study showed that the biological glue has favorable viscosity modifying effect on tissue engineering neural retina scaffolds, which is beneficial for the biological material transplantation. (Chin J Ophthalmol, 2018, 54: 277-282).

Analysis and comparison of the cost-effectiveness of statins according to the baseline low-density lipoprotein cholesterol level in Korea.

WHAT IS KNOWN AND OBJECTIVE: There are a few Korean studies on the economics of statins based on reduction in low-density lipoprotein cholesterol (LDL-C) data from other countries. This study aimed to analyse and compare the cost-effectiveness of statins according to the baseline LDL-C level in Korea. METHODS: Between January 2009 and December 2015, the data of patients who were prescribed statins for the first time were extracted from electronic medical records. We performed a cost-effectiveness analysis (CEA) based on the LDL-C reduction rate (CEA-RR) and target achievement rate. RESULTS AND DISCUSSION: Among high-intensity statins, the CEA-RR value of rosuvastatin (20 mg) was significantly lower than that of atorvastatin (40 mg) at all baseline LDL-C levels, except levels of 160-189 mg/dL. Additionally, at baseline LDL-C levels of 130-159 mg/dL, the CEA-RR value of rosuvastatin (20 mg) was three times lower than that of atorvastatin (40 mg) (9·1 ± 2·5 $/% vs. 31·7 ± 15·0 $/%, P < 0·001). Among moderate-to-low-intensity statins, rosuvastatin (5 mg) showed the lowest CEA-RR value (4·0 ± 0·6 $/%), and the value significantly increased for pitavastatin (2 mg) (8·0 ± 0·6 $/%), atorvastatin (10 mg) (9·5 ± 0·5 $/%), simvastatin (10·8 ± 1·1 $/%) and pravastatin (40 mg) (11·5 ± 0·9 $/%) in order (P < 0·0001). On changing from atorvastatin (10 mg) to atorvastatin (20 mg), the additional yearly cost was 16·0 and additional CEA-RR value was 2·74 $/%. On the other hand, on changing from atorvastatin (10 mg) to rosuvastatin (10 mg), the additional yearly cost was -16·3 and additional CEA-RR value was -1·8 $/%. WHAT IS NEW AND CONCLUSION: We successfully compared the cost-effectiveness of statins according to the baseline LDL-C level in Korea. It is expected that our findings will help clinical decision-making with regard to statin prescription, and this will help reduce national medical expenditure.

[Unprotected sexual intercourse and its correlates within HIV serodiscordant couples in Dehong prefecture of Yunnan Province, China, in 2014].

Objective: To study the prevalence and correlates of unprotected sexual intercourse within HIV serodiscordant couples in Dehong prefecture, Yunnan Province, China, in 2014. Methods: This study was based on the follow-up investigation of "the AIDS cohort of seronegative spouses of HIV-infected individuals in Dehong prefecture" in 2014. The 1 520 participants were HIV seronegative spouses from all five counties/cities of Dehong prefecture who voluntarily participated in the cohort. Inclusion criteria included: having a HIV-positive spouse; ≥16 years of age; having had sexual intercourse with spouse in the past year; and being a resident of Dehong prefecture. Information on HIV-positive spouses were also collected through the local AIDS epidemic database. Chi square analysis was performed to compare differences in the rates of unprotected sexual intercourse between participants with different characteristics and lifestyle choices. Multivariable logistic regression model analysis was performed to determine correlates with unprotected sexual intercourse. Results: The 1 520 participants had a mean age of 38.7±9.4, compared with 39.7±8.9 for their HIV-positive spouses. Among the HIV-positive spouses, 77.8% (1 183/1 520) had been infected for more than 3 years, and 87.6% (1 332/1 520) had received antiretroviral therapy. The prevalence of unprotected sexual intercourse within serodiscordant couples over the past 12 months was 16.1% (244/1 520). The prevalence of unprotected sexual intercourse correlated with the level of education of HIV-negative spouses (illiterate vs. middle school and above, OR=1.58, P=0.044), the number of years since diagnosis of HIV-positive spouses (short vs. long, OR=1.6, P=0.006), antiretroviral therapy of HIV-positive spouses (no vs. yes, OR=2.78, P<0.001), the frequency of sexual intercourse per month (high vs. low, OR=1.66, P=0.019), and whether the couple had children (no vs. yes, OR=1.72, P=0.007). Conclusion: The prevalence of unprotected sexual intercourse within serodiscordant couples in Dehong prefecture was relatively high in 2014. Factors found to correlate with the occurrence of unprotected sexual intercourse within these couples included illiteracy of HIV-negative spouses, short time since diagnosis of HIV-positive spouses and lack of antiretroviral therapy, high frequency of sexual intercourse and no children.

[Clinical and pathologic features of extrapleural sarcomatoid mesothelioma].

Objective: To investigate the morphological features, diagnosis and differential diagnosis of extrapleural sarcomatoid malignant mesothelioma (SMM). Methods: Six cases of extrapleural SMM were evaluated for their clinical, histological, immunohistochemical features, and prognosis. Results: Patients included 3 men and 3 women, with a median age of 60 years (range 41-75 years). All patients had no asbestos exposure in history and no pleural lesions. The tumors involved peritoneum (3 cases), bone (2 cases), and neck soft tissue (1 case). Histologically, the tumors were mainly composed of slender to plump spindle cells with occasional polymorphic cells, arranged in fascicular to storiform pattern or haphazardly organized, closely resembling those of fibromatosis, fibrosarcoma or malignant fibrous histiocytoma. The tumor cells were imunohistochemically positive for cytokeratin (pan, 6/6), calretinin (5/6), podoplanin (6/6), D2-40 (4/6), vimentin (6/6), WT1 (4/6), CD10 (3/6), SMA (4/6), and variably positive for CK7, and CK8/18, but were negative for other linage-specific markers. The Ki-67 proliferation indexes ranged from 25% to 55%, consistent with the diagnosis of malignant mesothelioma of the sarcomatous type. Ultrastructurally, the tumor cells possessed discontinuous external lamina, cytoplasmic processes, microfilaments and desmosomal intercellular junctions. Local recurrence or metastasis was seen in 1 case and 4 cases, respectively, after surgery, and all the patients died of the disease within 9 months. Conclusions: Extrapleural SMM, although rare, should be considered as a differential diagnosis among other benign or malignant sarcomatoid tumors and sarcomas. Along with clinical and radiological presentation, the combination of broad-spectrum cytokeratin, vimentin, and a series of mesothelial markers are useful for diagnosis of SMM.

[Role of master transcriptional factor Prox-1 in lymphatic endothelial differentiation of Kaposiform hemangioendothelioma].

Objective: To analyze the clinical and pathological features of Kaposiform hemangioendothelioma (KHE), and to investigate the role of master transcriptional factor Prox-1 in the regulation of lymphatic differentiation. Methods: Nine cases of KHE (during the period from October 2009 to June 2016) were collected with clinical and pathological data. H&E stained section review and immunohistochemietry using the Dako EnVision method were performed. Results: There were 6 female and 3 male patients with age ranging from 2 months to 8 years (median 3 years and 4 months). The patients presented with either single subcutaneous soft tissue mass, or bone tumors, with the duration of disease onset ranging from 1 month to 1 year. The sites of involvement included the skins of neck (2 cases), nose root (1 case), inguinal (1 case), thigh root (1 case), humerus (2 cases), lumbar vertebrae(1 case), and mesentery (1 case). These tumors were histologically composed of nodules of densely packed spindle or ovoid cells and deformed small blood vessels in an invasive growth pattern. The tumor cells were immunohistochemically positive for both blood vessels and lymphatic endothelial markers, including Prox-1, the master transcriptional factor, and VEGFR-3. With followed-up from 1 to 60 months (median 26 months), two patients died of the disease, while the remaining patients were alive without recurrence. Conclusions: KHE is a rare vascular tumor with at least partial lymphatic endothelial differentiation, in which Prox-1 may act as a master regulator for such differentiation. KHE is an aggressive tumor of intermediate malignant potential, with local invasion and recurrence tendency, and long term follow-up is required.